Despite detection of prostate cancer at earlier stages and advances in the treatment of local as well as metastatic disease, there will still be an estimated 28,170 deaths due to prostate cancer in 2012. Men who die of prostate cancer have cancers with aggressive pathologic features that increase the risk of tumor progression and metastasis, even if they undergo radical therapy with curative intent. As such, the investigation of novel strategies to prevent the development of aggressive or advanced prostate cancer will be critical to lowering the morbidity and mortality attributed to this disease.
Epidemiologic studies have described a positive correlation between high serum cholesterol level and prostate cancer aggressiveness (Platz et al. Cancer Epidemiol Biomarkers Prev. 18(11):2807-13 (2009)) as well as a protective effect of statin use in lowering the risk of advanced prostate cancer. Mondul et al., Cancer Causes Control. 21(5):671-8 (2010). These reports, along with the discovery of de novo androgen synthesis in castration resistant prostate cancer (CRPC), have fueled a renewed interest in intratumoral cholesterol homeostasis due to the central role of cholesterol in steroidogenesis. Furthermore, excess intracellular cholesterol is incorporated into membrane lipid rafts, thereby stabilizing the raft structure and enhancing AKT signaling in prostate cancer cells. Oh et al., Prostate. 67(10):1061-9 (2007). Therefore, examining how prostate cancer cells manipulate intracellular cholesterol content is important for understanding prostate cancer biology.
Perturbation in cholesterol homeostasis is a well-known characteristic of cancer that was described more than fifty years ago. Siperstein M D, Fagan V M., Cancer Res. 24:1108-15 (1964). Subsequently, anecdotal reports described a beneficial effect of cholesterol lowering agents in the management of prostate cancer. Addleman W., N Engl J. Med., 287(20):1047 (1972). The introduction and widespread use of statins as cholesterol lowering agents in the prevention of heart disease allowed the collection of epidemiological data correlating prostate cancer risk and statin use. Although meta-analyses showed that statins had no effect on the overall risk of prostate cancer (Browning D R, Martin R M., Int J. Cancer. 120(4):833-43 (2007), other studies have shown that statin use is associated with a decreased risk of aggressive or advanced prostate cancer. Murtola et al., Cancer Epidemiol Biomarkers Prev. 16(11):2226-32 (2007); Jacobs et al., Cancer Epidemiol Biomarkers Prev. 16(11):2213-7 (2007). Importantly, these cancers are potentially life threatening even after radical treatment. Thus, focusing on preventing the development or progression of aggressive prostate cancer is of utmost importance, and cholesterol may provide an opportune target. Indeed, recent reports suggest that statin use protects against prostate cancer with adverse pathologic characteristics (Mondul et al., J. Urol. 185(4):1268-73 (2011)) and improves progression free survival in men undergoing radiation therapy. Kollmeier et al., Int J Radiat Oncol Biol Phys. 79(3):713-8 (2011).